The pathogenesis of ischemic brain cell injury is poorly understood. Necessarily, the future prevention or amelioration of the consequences of ischemic brain cell injury must come from an improved understanding of the cellular mechanisms that result in irreversible cell damage. A highly reproducible (Cornell) model of severe ischemic brain damage in the rat has been developed in this laboratory and will be used in this study. Work with our ischemic model has shown a selective susceptibility of neurons in space and time. Pyramidal cells of the hippocampus can be grouped into susceptible (CA1 and CA 3-5) and resistant (CA 2) zones. Remarkably, cells in CA 1 show delayed histological deterioration which fails to begin until almost 24 hours after the ischemic period while cells in CA 3-5 progressively deteriorate starting immediately after the ischemic period. It is my hypothesis that ischemic brain injury results from the consequences of a loss of pH and calcium homeostasis in the brain. Two recent lines of work suggest that changes in cell calcium or tissue lactate may be fundamentally responsible for ischemic brain damage. However, data in the current literature as well as preliminary results from this laboratory suggest that the interrelation between pH and calcium homeostasis may be the mechanism which initiates the irreversible cell changes of brain ischemia. The objective of this investigation is to examine the electrical characteristics of and ion metabolite changes associated with hippocampal pyramidal cells after an ischemic insult. Microelectrodes sensitive to particular ions, chemicals, and gases (microsensors) will be used to monitor the cellular and adjacent microenvironment in CA 1 and CA 3-5 hippocampal neurons continuously during and after controlled ischemic episodes of 20 to 30 minutes. Measurements will be carried out for 24 hours or more following the transient ischemic exposure. Existing microsensors for sodium, potassium, calcium, pH, and chloride will be used in this study. In addition we expect to develop new sensors for carbon dioxide, oxygen, glucose, lactate, and glutamate.